title: CD8(+) T cell cross-reactivity profiles and HIV-1 immune escape towards an HLA-B35-restricted immunodominant Nef epitope.
abstract: Antigen cross-reactivity is an inbuilt feature of the T cell compartment. However, little is known about the flexibility of T cell recognition in the context of genetically variable pathogens such as HIV-1. In this study, we used a combinatorial library containing 24 billion octamer peptides to characterize the cross-reactivity profiles of CD8(+) T cells specific for the immunodominant HIV-1 subtype B Nef epitope VY8 (VPLRPMTY) presented by HLA-B(*)35∶01. In conjunction, we examined naturally occurring antigenic variations within the VY8 epitope. Sequence analysis of plasma viral RNA isolated from 336 HIV-1-infected individuals revealed variability at position (P) 3 and P8 of VY8; Phe at P8, but not Val at P3, was identified as an HLA-B(*)35∶01-associated polymorphism. VY8-specific T cells generated from several different HIV-1-infected patients showed unique and clonotype-dependent cross-reactivity footprints. Nonetheless, all T cells recognized both the index Leu and mutant Val at P3 equally well. In contrast, competitive titration assays revealed that the Tyr to Phe substitution at P8 reduced T cell recognition by 50-130 fold despite intact peptide binding to HLA-B(*)35∶01. These findings explain the preferential selection of Phe at the C-terminus of VY8 in HLA-B(*)35∶01(+) individuals and demonstrate that HIV-1 can exploit the limitations of T cell recognition in vivo.
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Motozono
authors.forename: John J
authors.initials: JJ
authors.lastname: Miles
authors.forename: Zafrul
authors.initials: Z
authors.lastname: Hasan
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Gatanaga
authors.forename: Stanley C
authors.initials: SC
authors.lastname: Meribe
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Shinichi
authors.initials: S
authors.lastname: Oka
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
authors.forename: Takamasa
authors.initials: T
authors.lastname: Ueno
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003429:Cross Reactions; D015693:Gene Products, nef / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D015797:HLA-B35 Antigen / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion; D016056:Immunodominant Epitopes / Q000276:immunology*
chemical_list: D015693:Gene Products, nef; D015797:HLA-B35 Antigen; D016056:Immunodominant Epitopes